tbuckley/cabot-search huggingface dataset:
Abstract 15261: Adipor2 Sirna-Mediated Knockdown Predominantly Polarizes Towards a M1 Phenotype in THP-1 Macrophages
Authors: Ioanna Gianopoulos, Styliani S Daskalopoulou
Journal: Circulation (2022)

Introduction: Monocyte-derived macrophages (Mϕs) are the major innate immune cells in plaques, where they assume a more pro-inflammatory (M1) or anti-inflammatory (M2) Mϕ phenotype. Notably, M1 Mϕs are more abundant in unstable plaques, while M2 in stable plaques. Adiponectin receptor 1 (AdipoR1) and AdipoR2 are highly expressed in the monocyte/Mϕ lineage and largely mediate immune responses. Herein, we investigated the specific contribution of AdipoR1 and AdipoR2 on polarization towards a M1 or M2 Mϕ phenotype. Methods: siRNA-mediated knockdown of AdipoR1 and/or AdipoR2 was performed in THP-1 monocyte-derived Mϕs, and collected to perform, 1) qRT-PCR analyses on AdipoR1 and AdipoR2, and 2) flow cytometry analyses on M1 Mϕ markers: CD86, CD80, MHC-II, and M2 Mϕ markers: CD206, CD163. Results: For qRT-PCR analyses, siRNA-mediated knockdown of single AdipoR1 and AdipoR2 significantly decreased the mRNA levels of their respective receptor (p&lt;0.01, p&lt;0.0001), while the opposing receptor was unaffected. Double knockdown resulted in a significant decrease in both AdipoR1 and AdipoR2 mRNA levels (p&lt;0.001, p&lt;0.0001). For flow cytometry analyses, single AdipoR1 and double AdipoR1/R2 siRNA led to a significant decrease in ΔMFI (mean fluorescence intensity) of MHC-II (p&lt;0.01), while a significant increase was observed in single AdipoR2 siRNA (p&lt;0.01). Intracellular siRNA-mediated knockdown of AdipoR1 and/or AdipoR2 did not result in a significant loss of their cell surface expression, as confirmed via dot plots analyses. Lastly, single AdipoR1 and double AdipoR1/R2 siRNA exhibited decreased % MHC-II/CD86-positive cells (p&lt;0.01, p&lt;0.001), while single AdipoR2 siRNA increased % MHC-II/CD86-positive cells (p&lt;0.05). Conclusions: Despite intracellular siRNA-mediated knockdown of AdipoR1 and/or AdipoR2, their cell surface expression remains intact. Furthermore, single AdipoR2 siRNA was associated with an increase in M1 Mϕ population (MHC-II/CD86), which is in line with our previous evidence showing decreased AdipoR2 signalling in unstable plaques. Thus, downregulation of AdipoR2 may play a role in polarization predominantly towards a M1 phenotype in THP-1 Mϕs and hence could be mechanistically relevant in the development of unstable plaques.
Abstract 15312: Automatic Left Atrial Volume and Sphericity Index Calculation From Cardiac CT Using Computer Graphics Imaging and Deep Learning
Authors: Ruibin Feng, Brototo Deb, Prasanth Ganesan, Fleur V Tjong, Albert J Rogers, Samuel Ruiperez-Campillo, Sulaiman Somani, Miguel Rodrigo, Paul L Clopton, James Zou, Matei Zaharia, Sanjiv M Narayan
Journal: Circulation (2022)

Introduction: Left atrial (LA) volume and sphericity index are important for atrial fibrillation (AF) recurrence prediction after ablation and AF-associated atrial remodeling analysis. However, calculating these indexes from computed tomography (CT) requires manual outlining, which is subjective and difficult to scale. Hypothesis: We hypothesized LA body can be "virtually" dissected from electroanatomic shells using computer graphics imaging (CGI). We further hypothesized that the results of virtual dissection can be used to train a deep learning (DL) model for automatic LA volume and sphericity index calculation. Methods: First, by encoding the anatomic knowledge with geometric modeling, we developed a mathematical method (termed "virtual dissection") based on CGI techniques to isolate the LA body from electroanatomic shells (Fig A). Second, we used virtual dissection to train a DL model to segment CTs in N=20 patient atria (Fig B-C). Finally, we used this pipeline to segment raw CTs in a test cohort of N=100 patients (30.0% women, 66.0±10.3Y; Fig D). Results: In the independent test cohort (N=100), the LA volume and sphericity index were automatically calculated from DL-based segmentation, with the agreement within 4.04 ml (95% CI: -11.48 to 19.55; r=0.98; p &lt; 0.0001; Fig E-F) and 2.75% (95% CI: -5.71 to 11.22; r=0.88; p &lt; 0.0001; Fig G-H), compared to expert annotation. Conclusions: Encoded anatomical knowledge combined with deep learning in small datasets can accurately extract 3D cardiac models from raw CT scans in large populations, yielding automatic calculation of indexes such as volume and sphericity. This computational pipeline may simplify the outcome analysis and prediction using geometric indexes as predictors.
Abstract 14674: Identifying CXCL12 as a Potential Marker for AF Subset Classification Based on Bioinformatic Tools
Authors: Lingzhi Yang, Wei Huang, Yunwei Chen
Journal: Circulation (2022)

Introduction: An improved understanding of the pathogenesis of AF and atrial substrate remodeling is necessary for development of novel therapeutic approaches and new management strategies. Hypothesis: CXCL12 could be involved in the regulation of AF inflammatory microenvironment and have the potential to be a marker for AF subset classification. Methods: In this study, we utilized the Robust Rank Aggregation method to integrate AF microarray datasets. Potential compounds were identified by mining the Connectivity Map database. Functional modules and closely-interacted clusters were identified using WGCNA analysis and PPI network, respectively. Biological functions were further analysed. Moreover, a reliable Machine Learning-based diagnostic model was constructed and visualized to clarify the diagnostic features of these genes. Results: Differentially expressed genes were identified. We showed that mitogen-activated protein kinase and epidermal growth factor receptor inhibitors were likely to mitigate AF based on Connectivity Map analysis. Four genes were identified as hub genes. CXCL12 was shown to play an important role in regulation of local inflammatory response and immune cell infiltration. Conclusions: Key genes involving in the pathogenesis of AF were identified. The biological features of CXCL12 in AF were investigated using integrative bioinformatics tools. The results suggested that CXCL12 might be a biomarker that could be used for distinguishing subsets of AF, and indicated that CXCL12 might be an important intermediate in the development of AF by increasing the infiltration of mast cells, neutrophils, and γδ T cells, and reducing infiltration of regulatory T cells. A reliable Machine Learning-based diagnostic model was constructed. Our work improved understanding of the mechanisms of AF predisposition and progression, and identified potential therapeutic avenues for treatment of AF.
Abstract 253: Decline In Initial Shockable Rhythm In Patients Treated With Public Access Defibrillators Over A 10-year Period
Authors: Hannah Torney, Olibhear McAlister, Sarah McQuaid, Adam Harvey, Amy Kernaghan, David McEneaney, Jennifer Adgey
Journal: Circulation (2022)

Introduction: Previous analysis of emergency medical services manual defibrillator recordings suggests that the proportion of patients with initial shockable rhythms during out-of-hospital cardiac arrest is decreasing over time. This analysis aims to determine if this decline also occurs in public access defibrillator data. Methods: Worldwide post-market data from HeartSine SAM PAD public access defibrillators was collected between 2012 and 2022. Presence of an initial shockable rhythm (ventricular fibrillation or ventricular tachycardia) was determined by the device algorithm decision and clinical overread. The proportion of patients who presented an initial shockable rhythm each year was calculated. Data was analysed using Minitab. Summary statistics were calculated for patient age and gender, and a logistic regression model was used to examine the proportion of initial shockable rhythm over time. Results: A total of 5404 patient events were collected. Seventy-four percent were male, and mean (SD) age was 61.2 (18.2) years. Proportion of initial shockable rhythm as a response to year was assessed, and occurrence of shockable rhythms decreased by approximately 6% per year [OR: 0.94, 95%CI (0.91, 0.96), p&lt;0.001]. Conclusion: In line with findings from emergency service resuscitation attempts, the proportion of initial shockable rhythms in patients treated with a public access defibrillator declined over a ten-year period.
Abstract 15706: Non-Invasive 3D Electromechanical Cycle Length Mapping for Macroreentrant Atrial Flutter Characterization
Authors: Melina Tourni, Elisa Konofagou
Journal: Circulation (2022)

Introduction: Arrhythmia localization prior to catheter ablation is critical for clinical decision making. The current standard of 12-lead EKG interpretation lacks spatial specificity and is anatomically limited. Electromechanical Cycle Length mapping (ECLM) is a high frame rate, echocardiography-based frequency analysis mapping technique, that can noninvasively map, localize and characterize cardiac activation frequencies in 3D. Hypothesis: Accurate localization prior to ablation may facilitate pre-op planning, reduce procedural times and fluoroscopic exposure. In this study we access ECLM feasibility for 3D mapping and quantifying macroreentrant atrial flutter (AFL) activation rates. Methods: Four patients (N = 4; 65 ± 9yo; 3 M) presented with AFL and were referred to RF ablation. Patients underwent pre-op transthoracic ECLM with simultaneous 3-lead EKG. 3D atrial ECLM cycle length (CL) maps were rendered and areas with arrhythmic CL were identified (100-330 ms). ECLM AFL and Ventricular CLs were defined as the dominant CL of the arrhythmic region and the region that remains synchronized with the ventricular activation respectively. ECLM findings were compared against identified origins and CLs on intracardiac electroanatomic mapping (EAM). Results: ECLM successfully identified and localized the presence of atrial typical CTI flutter in all four subjects when compared against successful RF ablation. An ECLM map in a CTI AFL case is shown on Fig. 1a with the CTI circuit in the right atrium. ECLM CLs exhibited excellent agreement with both the CL of the 3-lead EKG (Atrial CL: r 2 = 0.91, Ventricular CL r 2 = 0.99) and the EAM AFL CL (r 2 = 0.92). Conclusions: ECLM can localize, map and quantify the electromechanical CLs in AFL in excellent agreement with the clinical electrical CL rates and propagation patterns obtained by clinical albeit invasive procedures, providing thus a clinical noininvasive, non-ionizing mapping tool for RF ablation planning.
Abstract 15779: Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Neurons as Models for <i>Toxoplasma Gondii</i> Infection
Authors: Li-Min Ting, jiajia yang, Mariana Burgos Angulo, Thomas V McDonald, Kami Kim
Journal: Circulation (2022)

Introduction: Toxoplasma gondii infects all nucleated cells in warm-blooded vertebrates. Infection may be asymptomatic in healthy people but may result in the lifelong chronic persistence of cysts containing bradyzoites in specific tissues such as muscle and neurons. Hypothesis: Stem cell-derived neurons and cardiomyocytes will recapitulate the tissue-specific parasite-host interaction underlying chronic persistence in Toxoplasma infection. Methods: Human induced pluripotent stem cell-derived cardiomyocytes (iCMs), cardiac fibroblasts (iCFs) and neurons (iNEs) were used as biologically relevant models to study the interactions of T. gondii with human hosts in vitro . iCM, iCF and iNE were infected with T. gondii TypeI/III EGS strain (dual fluorescent stage-specific reporter strain: mCherry driven by SAG1 promoter and sfGFP driven by the LDH2 promoter). Results: We observed higher rate of bradyzoite formation in iCM and iNE, compared to iCF from the same donor at 72 hours post-infection by fluorescence microscopy of live cells and flow cytometry. Furthermore, we have analyzed the changes in the gene expression of host cells during Toxoplasma infection using high-throughput RNA-seq. Compared to uninfected iCMs, iCMs infected for 24 hours showed 1090 upregulated and 753 downregulated differentially expressed genes (DEGs); iCMs infected for 72 hours showed 1956 upregulated and 1253 downregulated DEGs. Compared to uninfected iCFs, iCFs infected for 24 hours showed 1654 upregulated and 1971 downregulated DEGs; iCFs infected for 72 hours showed 2742 upregulated and 1916 downregulated DEGs. In comparison to uninfected iNEs, iNEs infected for 24 hours showed 190 upregulated and 321 downregulated DEGs; iNEs infected for 72 hours showed 244 upregulated and 91 downregulated DEGs. Enrichment analysis of gene sets regulated by infection will be presented. Conclusions: Our in vitro generated human iCMs, iCF and iNEs have provided us a valuable tool for better understanding the impact on the host cells during Toxoplasma infection. A detailed analysis of validation and intervention of the top dysregulated genes in all different cell types will inform the design of potential therapeutic targets.
Abstract 14549: Malignant Anomalous LMCA With an Interarterial Course: <i>Atypical Presentation</i>
Authors: Preston Baker, Ahmed Elkaronyi, Amir Darki
Journal: Circulation (2022)

A 42-year-old healthy female presented to the emergency department with coughing and shortness of breath, complicated by syncope. Before loss of consciousness, the patient reported feeling lightheaded, but no chest pain or palpitations were appreciated. Following a negative work up for cardiogenic syncope, she was discharged home with a presumed diagnosis of vasovagal syncope. Over the next 12 months, the patient had recurrent episodes of shortness of breath followed by either a presyncopal prodrome or full syncopal episodes. Each episode came on with coughing and dyspnea without significant exertion. 18 months after the original event, she was re-evaluated for cardiac etiologies of her symptoms, and CT coronary angiogram showed an anomalous left main coronary artery arising from the right coronary cusp (AAOLCA) with an interarterial course, which was subsequently confirmed on coronary angiography (figure 1). Anomalous Left Coronary Arteries of Aortic Origin (AAOLCA) present a diagnostic dilemma for cardiologist, given their vague presenting symptoms, unknown prevalence in the general population, and high risk for Sudden Cardiac Death (SCD). This patient’s syncopal episodes and presyncopal symptoms that were inconsistent with a cardiac etiology represent an atypical presentation, although there is no classic presentation for which AAOLCA is the most likely diagnosis. AAOLCA’s with an interarterial course, as seen in this patient, account for the majority of SCD caused by anomalous coronary arteries, despite making up just 1.3% of all identified cases. Referral for surgical correction is recommended for all patients AAOLCA with an interarterial course, to reduce risk of SCD. Further research is warranted regarding the true prevalence of AAOLCA in the general population, the risk of SCD associated with various AAOLCA’s, and validated screening tools for utilization of coronary CTA or MRA to identify AAOLCA’s prior to major cardiac events.
Abstract 15660: Impaired Mitochondrial Quality Control Drives the Development of Cardiomyopathy in Anderson-Fabry Disease
Authors: Jessica Gambardella, Antonella Fiordelisi, Roberta Avvisato, Federica A Cerasuolo, Antonietta Buonaiuto, Nella Prevete, Cinzia Perrino, Valeria D'Argenio, Roberta Paolillo, Stefania D'Apice, Gaetano Santulli, Daniela Sorriento, GUIDO IACCARINO
Journal: Circulation (2022)

Introduction: Anderson-Fabry disease (AFD) is a systemic disorder caused by impaired alpha-galactosidase (GLA) activity, leading to a progressive cardiomyopathy, with hypertrophy and diastolic dysfunction. However, the molecular mechanisms underlying these features are unknown. Aim: To explore the role of mitochondria as a pathogenic mechanism of cardiac dysfunction in AFD. Methods: We tested a transgenic mouse that lacks endogenous GLA and expresses human R301Q-GLA [Tg/GLA knockout]. We performed serial ecochardiographic, histological, and biochemical analyses on cardiac tissue and single cell contractility on isolated adult cardiomyocytes (CM). Moreover, we assessed mitochondrial morphology/function in mouse embryonic fibroblasts (MEFs). Results: AFD-MEFs display an impaired mitochondrial respiration and reduced ATP synthesis. Increased mitochondrial levels of DRP1, LC3II, and MFN-ubiquitination along with accumulation of fragmented mitochondria and autophagosomes indicate the presence of mitophagy-targeted mitochondria that were not removed. Reduced PGC-1a and mitochondrial-DNA synthesis in AFD-MEFs indicate impaired mitochondrial biogenesis as well. Altogether, our data indicate impaired mitophagy and quality control of AFD-mitochondria. At echocardiography, AFD mice showed diastolic dysfunction and hypertrophy starting from 9 months. Isolated AFD-CMs exhibit reduced inotropic response to isoproterenol. Remarkably, alterations of cardiac mitochondrial function were observed starting from 3 months, including increased levels of MFN2-ubiquitination, DRP1 and LC3II, decreased levels of PGC-1a along with accumulation of disarranged mitochondria and autophagosomes. Frank impairment of mitochondrial respiration in AFD-CMs and reduced myocardial ATP-content was detected from 6 months, together with increased release of Cytochrome-C in the cytosol. Strikingly, mitochondrial dysfunction was also detected in fibroblasts isolated from AFD patients, which have a significantly reduced electron transport chain activity. Conclusions: In AFD, energetic alterations associated with impaired autophagy/mitophagy, are evident at 3 months and progressively lead to cardiac hypertrophy and dysfunction.
Abstract 14851: Risk Factors and Clinical Effects of Leaflet Thrombosis After Transcathether Aortic Valve Replacement
Authors: Minjung Bak, Sung-ji Park, KIHONG CHOI, Jihoon Kim, Taek Kyu Park, Eun Kyoung Kim, Sung Mok Kim, Seung-Hyuk Choi
Journal: Circulation (2022)

Introduction: The incidence of leaflet thrombosis is higher in TAVR than in SAVR; however, knowledge regarding the risk factors of leaflet thrombosis in TAVR is limited. Hypothesis: In this study, the incidence and risk factors for leaflet thrombosis after TAVR and its effects on clinical course were investigated. Methods: 176 patients who underwent TAVR from January 2015 to October 2020 were enrolled. Follow-up MDCT was performed between 3 months and 2 years after TAVR in 94 patients. Among the 94 patients, leaflet thrombosis occurred in 20 patients, and risk factors were analyzed by comparing clinical factors, echocardiographic parameters, 4D-MDCT information, and angiographic data between thrombosis group and no thrombosis group. Clinical outcome was defined as the composite of all-cause death, stroke, HF admission, redo AVR, and major bleeding after detection of leaflet thrombosis. Results: Indexed mean SOV diameter, AV calcium volume, and post-procedure EOAi were predictive of leaflet thrombosis with AUC value of 0.670 (95% CI 0.546 - 0.795, P -value = 0.020), 0.695 (95% CI 0.541 - 0.850, P -value = 0.012), and 0.665 (95% CI 0.548 - 0.782, P -value = 0.031), respectively. In echocardiography performed at the time of follow-up CT, the value of AV max velocity and AV mean pressure gradient were higher in the thrombosis group and the EOAi and Doppler velocity index values were lower in the thrombosis group than in the no thrombosis group. All the median echocardiographic values in both groups were within normal range. All patients with leaflet thrombosis were in subclinical status and half changed medication after detection. Clinical outcome was not significantly different between the two groups (log-rank P -value = 0.26). Conclusions: Larger indexed SOV diameter, higher AV calcium volume, and smaller post-procedure AV EOAi were risk factors for leaflet thrombosis after TAVR. Subclinical leaflet thrombosis has a benign course when properly managed.
Abstract 14553: Clonal Hematopoiesis of Indeterminate Potential is Associated With Atrial Fibrillation in Patients With Early Coronary Artery Disease
Authors: Nadia Akhiyat, Terra Lasho, Morsaleh Ganji, Michel T Corban, Ali Ahmad, Lilach O Lerman, Mrinal Patnaik, Amir Lerman
Journal: Circulation (2022)

Introduction: The mechanistic link between early coronary artery disease (CAD) and atrial fibrillation (AF) continues to be explored. Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a risk factor for cardiovascular disease. We hypothesize CHIP further increases the risk for AF in early CAD. Methods: 184 participants underwent invasive coronary angiogram with endothelial function testing. Buffy coat was used for whole exosome sequencing to identify CHIP (variant allele frequency &gt; 2% and minor allele frequency ≤ 0.1%). Early CAD was defined by the presence of coronary endothelial dysfunction (CED) in the absence of obstructive CAD. Invasive coronary angiography with endothelial function testing characterized CED as ≥ 20% increase in coronary artery diameter or ≤ 50% increase in coronary blood flow in response to acetylcholine. AF was identified by ICD-10 code or patient survey and confirmed by an independent investigator by chart review. Cox proportional hazard regression was adjusted for age, sex, and conventional cardiovascular comorbidities (hypertension, diabetes, and total cholesterol). Results: Of the 184 participants, we identified 23 cases with both early CAD and CHIP and 62 normal controls without CHIP or CAD. Case patients were significantly older (mean 60 ±9 vs 52 ±10 years, p = 0.004 years) and predominantly female (74% vs 81%, p = 0.506). AF was more likely among case participants when compared to normal controls (29% vs 10%, p = 0.036). Mean time to AF or last follow-up was 11 ±7 years. Case patients with both early CAD and CHIP were nearly 10 times more likely to develop AF when compared to normal controls in a Cox regression model adjusted for age, sex, and conventional cardiovascular comorbidities (HR 9.52, 95% CI 1.93 - 47.02, p = 0.006). The risk for AF was not significant if we defined cases by only the presence of CHIP (n = 30) or early CAD (n = 122). Conclusions: Patients with both CHIP and early CAD may have greater risk for developing AF beyond the presence of CHIP or CAD alone. Our findings suggest an added mechanistic role of CHIP that further increases the risk for AF in early CAD.